THREE LEVELS OF DEFENCE

Tissue/Interstitial Fluid: Bathes the tissues and cells – supplying them with nutrients and O2, and removes wastes• Some tissue fluid returns directly into the capillaries, but some drains back into the blood circulation through a network of lymphatic vessels -> Called Lymph and contains Leucocytes (WBC), pathogens and cell debris.

Lymphatic System – Role

Returns proteins that leak out of the blood, back into the blood

Role in defence (continuous movement of WBC allow for routine screen of body for foreign material)

Cell damage initiated• Mast cells can be stimulated by ruptured body cells and release histamine, as can circulating WBC called basophils• Histamine: promotes vasodilation in tissues (increases blood flow) and Increases permeability of capillaries so WBC can squeeze out to intracellular fluid more easily

• When activated, WBC (leukocytes) migrate into the region due to chemotaxis (following the source of the chemical signalling molecules)• Leukocytes (monocytes and neutrophils) come to area and phagocytose foreign material• Neutrophils are short lived and die in a few days to prevent the risk of being infected and spreading disease around body (This is why infected sites often accumulate pus- dead neutrophils)• Not all bacteria are killed as some have evolved ways to escape phagocyte

Distinguishing self from non-self• Foreign molecules on either the outer surface of invaders or the toxins or enzymes they secrete alert general defences• Even parts of a protein or a small toxin molecule can be enough to trigger an immune response• Anything that triggers an immune response is an antigen• These general defences identify non-self molecules that are characteristic of microbes but not host cells• These can include:• Peptidoglycan ,Chitin and Specific Protein sequences (eg, those found in the flagella)• More specific recognition (for a particular disease) can also occur (see level 3 for more detail)

Innate responses• Work for any disease/invader regardless of type• Not something learnt (past experience will not change response for next time)• Similar in both plants and animals

Fever and Pain• Some interleukins released by macrophages signal to hypothalamus (temperature regulator in brain)• Hypothalamus resets body temperature to higher than normal (eg 39oC)• This can restrict the functioning and reproduction of many pathogens (above optimum temperatures for their enzymes)• Some cytokines also cause drowsiness (lets body save energy for fighting invaders and repairing damaged tissue)

Complement• Approx 20 different kinds of small proteins involved in inflammation• Activated when they encounter a foreign body, eg bacteria• Act by:a. Binding to surface of bacteria and yeast to tag for detection and uptake by phagocytesb. Inducing chemotaxisc. Stimulate mast cells to release histamined. Membrane attack complex - form a structure to puncture membranes

Interferons• Released by virus infected cells• Act as warning signal from doomed cell to neighbours• Neighbours cause changes in surface of surrounding cells to help prevent infection and inducing virus resistance genes to be expressed

:star:LEVEL 3:STAR:SpecificAim- Stop this specific disease and prevent it in the future

Specific Adaptive Immunity

• Specific: develops due to contact with the particular pathogen• Memory

kill virus infected cells and cancerous cells (First formed in the bone marrow but move to the thymus gland to mature)• Helper T cells and regulatory T cells - help co-ordinate other lymphocytes in doing their roles

Telling Friend from Foe – MHC

• The human immune system achieves self-recognition through receptors on the cell surface called the Major Histocompatibility Complex (MHC)• Displays short polypeptides (antigens) to T cells• Polypeptides may be ‘Self’ or ‘Foreign’• These are detected via the T and B cell receptors

MHC class I• As proteins in normal cells are broken down, some small peptides (antigens) are loaded into the MHC class I proteins and presented on the surface• If the cell is normal, these antigens tell lymphocytes the cell is a normal ‘self’ cell• Due to genetic differences, every person will have different MHCI self signals so everyone’s MHCI signal is unique to that person (unless you have an identical twin)• If the cell mutates (tumour) or is infected by a virus, the proteins presented (and so destroyed) will change and the MHCI signal will be ‘non-self’

• B and T cells contain large numbers of identical copies of receptor proteins• Each is specific to a specific antigen• The large variety of signals that can be recognised (approx. 10 million) is due to random genetic changes in the antibody and receptor genes• This is the reason that some people are more or less susceptible to different diseases

Avoiding self-recognition• Due to the random generation of receptors, some will bind to self molecules• During maturation in the bone marrow or the thymus these cells are shown different ‘self’ antigens - If they don’t react, they continue to mature or If they do react (bind), they activate apoptosis• When this process does NOT work correctlyT or B cells will attack self-cells - the cause of autoimmune diseases

Humoral immunity• Comes from the idea of ‘humours’ which related to body fluids• B cells release antibodies that bind to pathogens in the body fluids

Antibodies• Antibodies (Ab): Proteins, called Immunoglobulins (Ig)• Produced by B Lymphocytes• Made in response to an Antigen and can recognise and bind Antigen• Highly specific (One Antigen = One Antibody)• Each antibody has at least two sites that can bind antigen – the Antigen Binding Site (variable regions)• Antigen binding sites are identical on each Antibody - requires complementary shape

Opsonisation• Antibodies stuck to an antigen target it for destruction and make it easier for phagocytes to find the antigen• Enhances phagocytosis

Isotypes (types of antibodies)• 5 different types (outlined on p196)• Different types are found in different areas of the body• Main ones of note are - IgE - involved in allergic reactions and IgG - released by effector and memory cells, most commonly passed from mother to child in breast milk

Humoral Immune Response• Each B cell can produce Antibodies against one specific Antigen• A mature B lymphocyte may carry ~100,000 Antibody molecules on the surface (identical)• Can bind to intact (non-processed/presented) Antigen• B cells can also act as APC to activate TH cells (see the Cell mediated response)• Acts on bacteria and viruses outside the cell• Toxins produced by bacteria• B cells need to be activated by an antigen• Of the millions of different immature B cells, only a few will be able to bind to the antigen (lock and key model to bind)• B cells can also engulf ‘foreign’ material and act as APC to activate the cell mediated response• Once bound, that B cell starts to rapidly divide and the numbers of that clone will increase• Multiplication is more effective with assistance by TH cells• These B cells will differentiate into either Plasma cells or Memory cells

Plasma Cells• Secrete Antibodies against a specific Antigen• Live a few days but produce ~2000 Ab molecules/second

Advantage of the Humoral Response?• Plasma cells take care of the immediate infection - Antibodies typically persist for about 28 days• Memory cells stay dormant in the body for months or years holding antibodies on their plasma membrane, waiting for an antigen to bind• If months later a second exposure occurs B memory cells rapidly divide and differentiate into plasma cells• Response much faster than initially (more memory B cells present than the original naive B cell pool) and often attack disease before symptoms occur

Cell Mediated Response

• Involves directly killing virally infected and cancerous cells by TC lymphocytes• Distinguish self from non-self by membrane bound cell receptors• Do not bind antigens directly but instead recognise MHC Class I signals to identify targets• Release powerful cytotoxins when they encounter a target cell - These include perforin and granzymes that work to induce apoptosis in the target cell• There is a great variety of different T cells, as with B cells• When activated (by binding an antigen and being activated by TH cells) they rapidly bind and differentiate into memory T cells and effector cells• Skin graft experiments in mice demonstrate that memory T cells exist• Memory T cells cause problems in organ transplants - Donor and recipients must be as closely matched as possible, Difficult as blood type must be compatible and 6 different MHC types should be as close a match as possible (with many alleles for each MHC type), Unless of course you have an identical twin…• Organ transplant recipients must take anti-rejection drugs for the rest of their life to ‘dumb down’ their immune system enough to not recognise the foreign cells (but still fight off diseases!)• TH cells act as helpers for both B cells and T cells (Release cytokines and other chemicals to cause activated (bound to a compatible antigen) B or T cells to multiply)• Regulatory T cells (Treg) modulate the immune response and may enhance or suppress the actions of other lymphocytes or phagocytes (Prevents the immune system overreacting to a stimulus)

Why not always jump straight to level 3?• Both B and T systems take time to mature• Innate response is to initially protect and manage the disease until the specific weapons can be developed

:STAR:LEVEL 1 :star:Non-specific: Aim to stop the pathogen entering the body in the first place.

Chemical defences• Skin releases chemicals that destroy or inhibit the growth of micro-organisms• Sweat and oil give skin a low pH (3 to 5)• Stomach acid is very low pH that kills most micro-organismsTears, saliva and mucus contain lysozyme that breaks down certain bacterial cell walls

Skin• Largest organ in the body• Tough physical barrier between outside and inside• Made of epithelial cells• If cut and blood vessels are damaged platelets become sticky and form a clot to plug the wound

Flushing away pathogens- Mucus membranes• Lines the Respiratory, Urinary, Reproductive and GI tract• Traps pathogens and dirt• In the respiratory tract, this mucus is then expelled by the cilia. This is then swallowed and pathogens destroyed by stomach acids

Normal Flora• Bacteria, fungi, and protozoa that don’t harm the host• Prevent growth of pathogens through competition for nutrients and space